CN106831662B - A kind of amido polyol is for fumidil and its synthetic method and application - Google Patents
A kind of amido polyol is for fumidil and its synthetic method and application Download PDFInfo
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- CN106831662B CN106831662B CN201611246217.6A CN201611246217A CN106831662B CN 106831662 B CN106831662 B CN 106831662B CN 201611246217 A CN201611246217 A CN 201611246217A CN 106831662 B CN106831662 B CN 106831662B
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- fumidil
- amido polyol
- amido
- polyol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
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- Organic Chemistry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to compound fields, and in particular to amido polyol has structure shown in formula I for fumidil for fumidil and its synthetic method and application, the amido polyol.The new derivative of fumidil provided by the present invention (amido polyol is for fumidil or fumidil amido polyol) has water-soluble and stability well.Preparation of the present invention and common fumidil bicyclohexane salt are subjected to treatment discovery close to consistent bee colony of falling ill to sporidiosis under comparable sodium, amido polyol of the present invention is almost the same for fumidil therapeutic effect and common fumidil bicyclohexane salt effect, since the amido polyol is for the residual for not having bicyclohexane in fumidil, the risk to honeybee and human health is reduced.In addition to this, the dissolubility and stability of the product are more preferable.
Description
Technical field
The present invention relates to organic compound fields, and in particular to a kind of amido polyol is for fumidil and its synthetic method
With application.
Background technique
Fumidil (Fumagillin) separates in the fermentation culture by aspergillus fumigatus (Aspergillus fumigatus)
Obtain a kind of metabolite with various active.This substance has antibiotic activity, and has inhibition angiogenesis function, from
And there is the therapeutic effect to tumour growth.In addition, a series of derivatives of fumidil, which also have, resists plasmodium and spore
The effect of worm.Being very effective for fumidil treats apis mellifera sporidiosis (Nosema apis) in apiculture
Drug, in the country such as America & Canada using there is nearly 60 years history.It is that currently the only can effectively to treat honeybee micro-
The drug of sporozoite.But due to itself poorly water-soluble, need to be transformed into fumidil cyclohexylamine salt (predominantly
Dicyclohexylamine bicyclohexane) improve water-soluble and stability.There is scientist to find cyclohexylamine residual recent years
There is certain toxicity to honeybee, in addition, its stable structure, can accumulate in the bee products such as beeswax, it is difficult to degrade, to ring for a long time
Border and human health also bring potential risk, are badly in need of new drug or by other methods, obtain it is highly-safe, water-soluble and
The derivative of the good fumidil of stability treats Nosema apis parasitosis.
Since almost water is insoluble for fumidil, and easy illumination degrading, influence its biological utilisation, it is necessary to use reasonable side
Method increases the water solubility and stability of drug, to improve its bioavilability.
Summary of the invention
The first object of the present invention is to provide a kind of new derivative of fumidil, specifically, providing one kind such as
Amido polyol shown in formula (I) is for fumidil:
(amido polyol is more for fumidil or fumidil amido for the new derivative of fumidil provided by the present invention
First alcohol) there is water-soluble and stability well, fumidil cyclohexylamine salt is compared, honeybee palatability is good, and toxicity reduces, and produces
There is no cyclohexylamine residual in product.
The second object of the present invention is to provide above-mentioned amido polyol for the synthetic method of fumidil, and synthetic route is such as
Under:
Specifically: described in fumidil and amido polyol reacts at salt (forming carboxylate) in methanol solution and are generated
Amido polyol is for fumidil.
The present invention uses fumidil and amido polyol to prepare amido polyol for fumidil, preparation process for raw material
Simply, it is able to carry out mass production and preparation, and the advantages that product dissolubility is good nontoxic.
Preferably, the synthetic method are as follows: mix fumidil with amido polyol, in 50 DEG C~60 DEG C heating water baths
Under be gradually added into methanol solution until fumidil sufficiently dissolve, be maintained under bath temperature and stir 1~3 hour, be evaporated reaction
Mixed liquor is to get the amido polyol for fumidil.
It is further preferred that the molar ratio of the fumidil and amido polyol is 1.0~1.2, preferably 1:1.
Amido polyol of the present invention can be commercially available, but more preferably uses KBH4It is passed through with hydrochloric acid amido glucose
The reaction for forming carboxylate is made, to realize more industrial mass production.
Preferably, the synthetic method of the amido polyol is specific as follows: after reducing agent is dissolved in sodium hydroxide solution
It is gradually added dropwise in hydrochloric acid amido glucose, reacts at room temperature, detect reaction process with TLC, acetic acid is added after fully reacting and is quenched
Reaction, after reaction solution is washed with methanol repeatedly, distillation and concentration to obtain the final product.
It is preferred that the reducing agent is selected from KBH4、NaBH4、LiAlH4And Pd/H2, the more preferable reducing agent is KBH4。
Wherein, the molar concentration of sodium hydroxide solution is preferably 0.04~0.1mol/L, relative to KBH4Dosage with
Sufficiently being dissolved is advisable, such as 0.05mol/L.
Preferably, the reaction time was at 3~5 hours.
Amido polyol is prepared with easy to operate, the ideal advantage of the yield and purity of product using the above method.
The third object of the present invention is that providing the amido polyol prevents and/or treat honey in preparation for fumidil
Application in the drug of bee microsporidiosis.
When being used to prevent and/or treat Nosema apis parasitosis for fumidil for amido polyol of the present invention, tool
There is ideal control efficiency.
The present invention additionally provides a kind of for preventing and/or treating the pharmaceutical preparation of Nosema apis parasitosis, packet simultaneously
The fumidil amido polyol for including syrup and being dissolved in syrup.
Amido polyol of the present invention is dissolved in after syrup for fumidil and is used further to prevent and/or treat honeybee
When microsporidiosis, the water solubility and stability of drug can be further increased, there is better healing effect, while defined
The advantages of use in off-drug period, fumidil residue degrading is at nontoxic metabolin.
Preferably, the amido polyol is 15-30mg/L for content of the fumidil in the syrup, preferably
21mg/L.In above-mentioned content range, it can be ensured that effectively prevention sporidiosis realizes that bee colony is maintained in morbidity season infection rate
3% hereinafter, do not cause disease substantially.
By preparation of the present invention and common fumidil bicyclohexane salt under comparable sodium, sporidiosis is connect
Nearly consistent bee colony of falling ill is treated, and experimental result discovery, amido polyol of the present invention is for fumidil therapeutic effect
It is almost the same with common fumidil bicyclohexane salt effect, since the amido polyol is not for having two rings in fumidil
The residual of hexane reduces the risk to honeybee and human health.In addition to this, the dissolubility and stability of the product are more preferable.
Detailed description of the invention
Fig. 1: nuclear magnetic spectrum of the amido polyol described in embodiment 1 for fumidil.
Specific embodiment
The present invention is described further with reference to the accompanying drawings and examples.
Embodiment 1:
Amido polyol shown in formula I is present embodiments provided for fumidil:
Its nuclear magnetic spectrum is shown in Fig. 1.
Embodiment 2
A kind of method for synthesizing amido polyol is present embodiments provided, synthetic route is as follows:
Specific steps are as follows:
By 1.0g KBH4It is dissolved in and is gradually added dropwise after the solution of 17ml sodium hydroxide (0.05M) in the hydrochloric acid that 1.0g is housed
It will appear a large amount of bubble in the round-bottomed flask of amido glucose, in adition process (if high temperature increases, to need acutely to stir
It mixes, and is slowly added to).After reacting 2.5h at room temperature, reaction process is detected with TLC, if fully reacting, acetic acid is added and is quenched
Reaction.
After reaction solution is washed with methanol repeatedly, distillation and concentration obtains white solid, and yield is greater than 95%, and purity is
98%.
Embodiment 3
The present embodiment is also provided that a kind of method for synthesizing amido polyol, and compared with Example 2, distinctive points are only that
Individual operations parameter is different, specifically: NaBH is added4、LiAlH4Or Pd/H2Reducing agent substitutes KBH4。
The yield of product obtained by the present embodiment is 80%-90%, and purity is 95% or more.
Embodiment 4
A kind of synthesis amido polyol is present embodiments provided for the method for fumidil, synthetic route is as follows:
Operating procedure is as follows:
The amount of fumidil and amido polyol molar ratio 1:1 are added in round-bottomed flask, are placed in 50 DEG C of water-bath
In pot, it is then gradually added into methanol solution, until white powder gradually dissolves, keeps stir 2 hours under bath temperature, then general
Obtained reaction mixture is evaporated in Rotary Evaporators under the conditions of being protected from light, and obtains fumidil amino polybasic alcoholic compound, is produced
Rate is greater than 90%, purity 90%.
Embodiment 5
A kind of preparation containing amido polyol described in embodiment 1 for fumidil is present embodiments provided, it is specially sugared
Agent is starched, is dissolved in syrup and is formed for fumidil by amido polyol, the fumidil amido polyol is in the syrup
In content be 21mg/L.
Embodiment 6
The present embodiment is also provided that a kind of preparation containing amido polyol described in embodiment 1 for fumidil, with reality
It applies example 5 to compare, distinctive points are only that amido polyol described in the present embodiment is for content of the fumidil in the syrup
15mg/L。
Embodiment 7
The present embodiment is also provided that a kind of preparation containing amido polyol described in embodiment 1 for fumidil, with reality
It applies example 5 to compare, distinctive points are only that amido polyol described in the present embodiment is for content of the fumidil in the syrup
30mg/L。
Experimental example 1
This experimental example demonstrates amido polyol of the present invention for fumidil for treating honeybee sporidiosis
Application effect.
Experimental subjects:
Experimental group 1-3: syrup provided by embodiment 5-7；
Control group 1: the fumidil bicyclohexane salt (being dissolved in the syrup of 5L) of comparable sodium；
Control group 2: Protostat disclosed in the prior art.
Experimental method:
Three kinds of drugs are used to treat the bee colony of spore insect infection, the gradient of infection of three groups of bee colonies is confirmed by inoculation,
Gradient of infection is substantially suitable.To three groups of bee colony medicine feeds, sample is acquired after three days, observes bee colony situation, and calculate spore insect infection
Situation is collected simultaneously honey sample.
Experimental result:
Experimental result finds that amido polyol obtained by the present invention is (i.e. common for fumidil therapeutic effect and control group 1
Fumidil bicyclohexane salt) almost the same (wherein experimental group 1, i.e. syrup therapeutic effect described in embodiment 5 are most for effect
It is good), and it is higher than control group 2 (metronidazole treatment group), but amido polyol obtained by the present invention is not for having two in fumidil
The residual of hexamethylene reduces the risk to honeybee and human health.And in control group 1, the residual of bicyclohexane is dense in honey
Degree is up to 200mg/kg, and to honeybee and human-body safety, there are risks.
Experimental example 2
Take two kinds of drugs of comparable sodium (content of fumidil original shape is consistent): amido polyol is for fumidil and cigarette
Each 100mg of aspergillin bicyclohexane salt is dissolved in the 1L honey of equivalent, is placed in room temperature, every the fumidil of measurement in 12 hours
The content of original shape, the concentration of fumidil original shape is almost the same in first 24 hours, two drugs, reduces 20% or so；
But at 36,48,60,72 hours, amido polyol is kept at 75% for the original shape content of fumidil in fumidil,
55%, 45% and 42%；And the original shape content for corresponding to fumidil in time fumidil bicyclohexane salt is kept at
72%, 43%, 32% and 30%；Preferably stablize the result shows that the amido polyol of synthesis has in honey for fumidil
Property, it can persistently play a role.
In addition, by measurement catabolite, amido polyol for fumidil main metabolites in addition to aspergillus fumigatus cedrol and
Two photolytic products of fumidil, there are also amino polyol, amino polyol itself belongs to the metabolism of the biological cortex such as insect
Component, it is nontoxic to biology and environment, so drug of the invention has better safety.Embodiment in above-described embodiment
It can be further combined or replace, and embodiment is only that the preferred embodiment of the present invention is described, not to this hair
Bright conception and scope is defined, under the premise of not departing from design philosophy of the present invention, professional and technical personnel in the art couple
The various changes and modifications that technical solution of the present invention is made, all belong to the scope of protection of the present invention.
Claims (11)
1. a kind of amido polyol is for fumidil, which is characterized in that have structure shown in formula I:
2. amido polyol described in claim 1 is for the synthetic method of fumidil, it is characterised in that: synthetic route is as follows:
Specifically: fumidil and amido polyol generate the amido polyol for cigarette song through salt-forming reaction in methanol solution
Mycin.
3. synthetic method according to claim 2, it is characterised in that: mix fumidil with amido polyol, 50
DEG C~60 DEG C of heating water baths under be gradually added into methanol solution until fumidil sufficiently dissolve, be maintained under bath temperature and stir 1
~3 hours, reaction mixture was evaporated to get the amido polyol for fumidil.
4. synthetic method according to claim 3, it is characterised in that: the molar ratio of the fumidil and amido polyol
It is 1.0~1.2.
5. according to the described in any item synthetic methods of claim 2-4, it is characterised in that: the amido polyol is by KBH4And salt
Acid amide base glucose is made through salt-forming reaction.
6. according to the described in any item synthetic methods of claim 2-4, it is characterised in that: the synthetic method of the amido polyol
It is specific as follows:
Reducing agent is dissolved in after sodium hydroxide solution and is gradually added dropwise in hydrochloric acid amido glucose, reacts at room temperature, is detected with TLC
Acetic acid quenching reaction is added in reaction process after fully reacting, after reaction solution is washed with methanol repeatedly, distillation and concentration to obtain the final product.
7. synthetic method according to claim 6, it is characterised in that: the reducing agent is selected from KBH4、NaBH4、LiAlH4With
Pd/H2。
8. amido polyol described in claim 1 prevents and/or treats the medicine of Nosema apis parasitosis in preparation for fumidil
Application in object.
9. a kind of for preventing and/or treating the pharmaceutical preparation of Nosema apis parasitosis, it is characterised in that: including syrup and molten
As described in claim 1 amido polyol of the solution in syrup is for fumidil.
10. pharmaceutical preparation according to claim 9, it is characterised in that: the amido polyol is for fumidil described
Content in syrup is 15-30mg/L.
11. pharmaceutical preparation according to claim 10, it is characterised in that: the amido polyol is for fumidil described
Content in syrup is 21mg/L.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611246217.6A CN106831662B (en) | 2016-12-29 | 2016-12-29 | A kind of amido polyol is for fumidil and its synthetic method and application |
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| CN201611246217.6A CN106831662B (en) | 2016-12-29 | 2016-12-29 | A kind of amido polyol is for fumidil and its synthetic method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109867639A (en) * | 2017-12-01 | 2019-06-11 | 中国农业科学院农业质量标准与检测技术研究所 | The method for preparing fumidil amido alcohol |
| CN109867637A (en) * | 2017-12-01 | 2019-06-11 | 中国农业科学院农业质量标准与检测技术研究所 | The preparation method of fumidil amido alcohol |
| CN109867640A (en) * | 2017-12-01 | 2019-06-11 | 中国农业科学院农业质量标准与检测技术研究所 | A kind of preparation method of fumidil amido alcohol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2718488A (en) * | 1953-12-17 | 1955-09-20 | Abbott Lab | Amine salts of fumagillin |
| CN101990441A (en) * | 2007-11-28 | 2011-03-23 | 默萨那治疗学股份有限公司 | Biocompatible biodegradable fumagillin analog conjugates |
| CN105622593A (en) * | 2016-02-25 | 2016-06-01 | 中国农业科学院蜜蜂研究所 | Extraction method of fumagillin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6803382B2 (en) * | 2001-11-09 | 2004-10-12 | Galderma Research & Development, S.N.C. | Angiogenesis inhibitors and pharmaceutical and cosmetic use thereof |
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2016
- 2016-12-29 CN CN201611246217.6A patent/CN106831662B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2718488A (en) * | 1953-12-17 | 1955-09-20 | Abbott Lab | Amine salts of fumagillin |
| CN101990441A (en) * | 2007-11-28 | 2011-03-23 | 默萨那治疗学股份有限公司 | Biocompatible biodegradable fumagillin analog conjugates |
| CN105622593A (en) * | 2016-02-25 | 2016-06-01 | 中国农业科学院蜜蜂研究所 | Extraction method of fumagillin |
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